Tip60-mediated lipin 1 acetylation and ER translocation determine triacylglycerol synthesis rate

Li, Terytty Yang; Song, Lintao; Sun, Yu; Li, Jingyi; Yi, Cong; Lam, Sin Man; Xu, Duanyi; Zhou, Linkang; Li, Xiaotong; Yang, Ying; Zhang, Chen-Song; Xie, Changchuan; Huang, Xi; Shui, Guanghou; Lin, Shu-Yong; Reue, Karen

doi:10.1038/s41467-018-04363-w

Cited by 54 publications

(59 citation statements)

References 49 publications

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“…Moreover, genome-wide RNAseq shows remarkably stable gene transcription between affected and unaffected animals. This suggests the second hit acts on Lipin by a post-translational mechanism; in fact consistent with the complex post-translational regulation of Lipin enzymes (Eaton et al, 2013; Harris et al, 2007; Hsieh et al, 2015; Li et al, 2018; Liu and Gerace, 2009). Additional work is needed to dissect which pathways regulate Lipin during brain development, how they are affected by developmental events and stresses, and their relationship to sex.…”

Section: Discussionsupporting

confidence: 67%

Lipid metabolic stress in development defines which genetically-susceptible DYT-TOR1Amice develop disease

Cascalho

Foroozandeh

Rous

et al. 2020

Preprint

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SummaryThere has been enormous progress defining the genetic landscape of disease. However, genotypes rarely fully predict neurological phenotypes, and we rarely understand why. TOR1A +/Δgag that causes dystonia with ~30% penetrance is a classic case. Here we show, in inbred mice, that +/Δgag affects embryonic brain lipid metabolism with sex-skewed reduced penetrance. Penetrance is affected by environmental context, including maternal diet. The lipid metabolic defect resolves during post-natal development. Nevertheless, we discover dystonia-like symptoms in ~30% of juvenile female Tor1a+/Δgag mice, and prevent these symptoms by genetically suppressing abnormal lipid metabolism. We conclude that Tor1a+/Δgag embryos poorly buffer metabolic stress in utero, resulting in a period of abnormal metabolism that hardwires the brain for dystonia in later life. The data show unexpected and profound impacts of sex, and thus highlight the importance of examining male and female animal models of disease.Significance StatementThe genetic landscape of neurological disease is relatively well mapped. However, we typically cannot explain why some mutations only cause disease in a subset of individuals. A classic case is DYT-TOR1A dystonia that only develops in 30% of TOR1A+/Δgag carriers. We now find that ~30% of inbred female Tor1a+/Δgag mice develop abnormal brain lipid metabolism as embryos, while males are spared. The percentage is affected by maternal diet. Further, this period of abnormal lipid metabolism causes dystonia-like symptoms in juvenile mice. These data show how an environmentally-sensitive event of development defines which genetically-susceptible individuals develop disease in later life. They also highlight the importance of examining male and female animal models of disease.

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Section: Discussionsupporting

confidence: 67%

Lipid metabolic stress in development defines which genetically-susceptible DYT-TOR1Amice develop disease

Cascalho

Foroozandeh

Rous

et al. 2020

Preprint

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“…6f). Also, the SUMOylation 41 and acetylation 42 Lipin-1 mutants were inactive in the same assay ( Supplementary Fig. 6a).…”

Section: Lipid Synthesis Contributes To the Beneficial Effects Of Rocmentioning

confidence: 78%

Extracellular matrix mechanical cues regulate lipid metabolism through Lipin-1 and SREBP

et al. 2019

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ach tissue has a specific composition of its extracellular matrix (ECM), which is associated with distinctive physical and mechanical properties. These mechanical properties are important for tissue structure, but also control cell function in physiology and disease 1,2. Cells sense the mechanical properties of the ECM through integrin receptors, and measure them by adjusting the contractility of their F-actin cytoskeleton: contractility is maximal when cells are free to spread on stiff ECM substrata, while it is progressively decreased on a soft ECM or in conditions of limited spreading 1. This is sufficient to control the switch between proliferation, differentiation and death in very diverse cell types, by regulating intracellular signalling pathways such as YAP (Yes-associated protein)/TAZ (transcriptional co-activator with PDZ-binding motif, also known as WWTR1) 3,4 and SRF (serum response factor) 5,6. In support of this model, inhibition of key players that maintain F-actin contractility including the small GTPase RHO, ROCK (RHO kinase), MLCK (myosin light chain kinase) and non-muscle myosin (NMII) induce similar responses to a soft ECM 1. Yet, which other general aspects of cell biology are regulated by mechanical cues, and through which mechanism(s), remain largely unexplored. This is especially true in the case of metabolism, a fundamental engine that is constantly remodelled to match the energetic and biosynthetic requirements of the cell, whose connections to mechanical cues are only starting to emerge 7,8. Results Actomyosin regulates lipid metabolism. To test in an unbiased manner the possibility that actomyosin contractility regulates metabolism we used global metabolomics to compare cells in conditions of high contractility (plated on plastics) with cells in conditions of low contractility, by inhibiting ROCK and MLCK. Analysis of steady-state levels of multiple metabolites indicated clear differences between controls and treated cells (Fig. 1a and Supplementary

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“…Immunoblot analyses of carnitine palmitoyltransferase I (CPT1), a mitochondrial enzyme that catalyzes the biosynthesis of acyl carnitines by transferring the acyl group of a long-chain fatty acyl-CoA from coenzyme A to l-carnitine [21], demonstrated significantly decreased levels of CPT1 during infection and HFD further affecting the levels (Figure 2(f)). Lipin 1, a critical regulator of intermediary fat metabolism, acts as a lipid phosphatase to dephosphorylate phosphatidic acid to form diacylglycerol-a key step in glycerolipid metabolism and triglyceride synthesis [22] was also significantly decreased in infected HFD mice compared to other groups (Figure 2…”

Section: Effect Of Diet On Hepatic Lipid Metabolism Duringmentioning

confidence: 99%

Diet Alters Serum Metabolomic Profiling in the Mouse Model of Chronic Chagas Cardiomyopathy

Lizardo¹,

Ayyappan²,

Ganapathi³

et al. 2019

Disease Markers

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Chagas disease is caused by Trypanosoma cruzi which is endemic in Latin America. T. cruzi infection results in a latent infection with approximately a third of latently infected patients developing chronic Chagas cardiomyopathy (CCM). CCM is a common cause of cardiomyopathy in endemic regions and has a poor prognosis compared to other cardiomyopathies. The factors responsible for the transition from the asymptomatic indeterminate latent stage of infection to CCM are poorly understood. Our previous studies demonstrated that lipid metabolism and diet are important determinants of disease progression. In the present study, we analyzed various serum metabolomic biomarkers such as acylcarnitines, amino acids, biogenic amines, glycerophospholipids, and sphingolipids in murine models of CCM, where the mice specifically develop either left or right ventricular cardiomyopathy based on the diets fed during the indeterminate stage in a murine model of Chagas disease. Our data provide new insights into the metabolic changes that may predispose patients to CCM and biomarkers that may help predict the risk of developing cardiomyopathy from T. cruzi infection. Author Summary. Chronic Chagas cardiomyopathy (CCM) is a parasitic disease prevalent in Latin America. Currently, no effective drugs or vaccines are available to prevent or cure CCM. The factors involved in the disease severity and progression are poorly understood to design new therapeutic interventions. In order to rapidly identify Chagas patients with a higher risk to develop CCM, a new set of biomarkers specific to Chagas disease is needed. We performed serum metabolomic analyses in chronic T. cruzi-infected mice fed on different diets and identified cardiac ventricular-specific metabolite biomarkers that could define CCM severity. In this paper, we present the results of serum metabolomic analyses and discuss its correlations to the diet-induced metabolic regulations in the pathogenesis of CCM in a murine model of Chagas disease.

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Tip60-mediated lipin 1 acetylation and ER translocation determine triacylglycerol synthesis rate

Cited by 54 publications

References 49 publications

Lipid metabolic stress in development defines which genetically-susceptible DYT-TOR1Amice develop disease

Lipid metabolic stress in development defines which genetically-susceptible DYT-TOR1Amice develop disease

Extracellular matrix mechanical cues regulate lipid metabolism through Lipin-1 and SREBP

Diet Alters Serum Metabolomic Profiling in the Mouse Model of Chronic Chagas Cardiomyopathy

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